Zia Gharib, Farzin; (1991) Amino acid neurotransmission during chemically-induced epileptogenic activity in the rat cerebral cortex. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This project was undertaken firstly to establish a relationship between chemically-induced epileptogenic activity and the release of amino acid neurotransmitters and secondly to try to compare the enhancement of γ-aminobutyric acid (GABA)-mediated inhibition with the blockade of excitatory amino acid receptors in the control of epileptogenic activity in rat cerebral cortex. Using cortical cups incorporating platinum electrodes, it was possible to monitor epileptogenic activity in the electroencephalogram (EEG), quantified using a specially designed voltage integrator, at the same time as studying the release of endogenous amino acids. In vitro release studies were performed using cortical slices (0.4mm) in a continuous superfusion system. An automated high performance liquid chromatography (HPLC) procedure was employed to determine amino acid levels in the perfusates. Bicuculline methiodide (BM) was chosen as the test convulsant to evaluate the relative importance of different amino acid receptors in the initiation and maintenance of epileptogenic activity in the rat cerebral cortex. EEG spiking was induced in urethane-anaesthetised rats by transient superfusion of BM across the exposed parietal cortex. Extracellular recording of a group of superficial cortical cells directly beneath the cup revealed that each interictal spike coincided with the sudden, synchronous burst firing of a group of cortical neurones. Compounds which enhance the action of GABA or block the excitatory amino acid receptors reduced such epileptogenic activity. GABAA receptor augmentation by muscimol and clonazepam reduced the size and, therefore, the severity of spiking whereas the GABAB agonist, baclofen, affected spiking by reducing the total number of spikes. NMDA blockade lead to a GABAA-like effect and only reduced the size of the spikes whilst non-NMDA receptor blockers reduced the number of spikes with little effect on their size. Since intravenous infusion of pentylenetetrazole (PTZ) had been shown to lead to epileptogenic activity in urethane-anaesthetised rats its effect on the efflux of various amino acids from the cortex was monitored. Only glutamine release was in fact enhanced during seizure-like activity. Direct cortical superfusion of PTZ lead to an unspecific release of most amino acids. By contrast in cortical slices PTZ only increased the release of the neurotransmitter amino acids GABA, glutamate and aspartate, plus taurine. When BM was superfused across the cortex in concentrations producing spiking it had no effect on the release of amino acids whereas it induced the release of GABA, glutamate and aspartate from cortical slices but only in the presence of p-chloromercuriphenylsulphonic acid (PCMS). The bicuculline-induced release of amino acid neurotransmitters was Ca++-dependent and it was reduced by the excitatory amino acid receptor antagonists. The EEG studies together with release data show a close relationship between amino acid neurotransmitters and cortical epileptogenic activity. The results of the studies on amino acid manipulation also imply that a number of amino acid-related effects are involved in the initiation and severity of epileptogenic activity. Hence a clear understanding of their roles could facilitate a better use of drugs alone or together, in the control of epileptogenic activity.

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